Inducing metabolic catastrophe in cancer cells


Inducing metabolic catastrophe in cancer cells
Eliminating HK2 (shown here), which is a key enzyme for glucose metabolism, may be a way to prevent cancer cells from surviving, according to a new study in JCB

A study published in The Journal of Cell Biology describes a way to force cancer cells to destroy a key metabolic enzyme they need to survive.

Cancer cells survive the stressful environment inside a tumor in part through autophagy, the controlled digestion and recycling of damaged components. However, blocking the process doesn’t kill , so researchers have been looking for a way to make cells vulnerable to autophagy shutdown.

Researchers at Harvard Medical School in Boston used an cell line that is resistant to the autophagy inhibitor spautin-1 or an upgraded version of this molecule. After screening more than 8,200 compounds, they found that quizartinib was the most effective at enhancing the cells’ vulnerability to either of the autophagy blockers. Quizartinib inhibits FLT3, an enzyme that is important for the normal development of and a validated target for (AML). The drug is currently in clinical trial for treatment of AML, but its value beyond has not been well explored.

The team found that quizartinib and the improved version of spautin-1 killed from a variety of cell lines while leaving noncancerous cells unscathed. Treating cancer cells with quizartinib alone inhibited an important metabolic pathway, glycolysis, and activated macroautophagy, the best known type of autophagy in which the cell digests a large portion of its contents. In contrast, cells that received both compounds couldn’t initiate macroautophagy, but they switched on chaperone-mediated autophagy, a selective form of the process that eliminates individual molecules.

One of its targets was the enzyme Hexokinase2 (HK2), which is crucial for glucose metabolism and is often overexpressed in cancer cells. By eliminating HK2, quizartinib and the autophagy inhibitor may prevent cancer cells from metabolizing absorbed glucose and mobilizing stored nutrients, thereby triggering cancer cell death. The study provides evidence that combining an FLT3 inhibitor with an autophagy blocker could be a new way to treat cancer.

Gold-plated nano-bits find, destroy cancer cells.


Carl Batt

Batt
Dickson Kirui

Kirui

Comparable to nano-scale Navy Seals, Cornell scientists have merged tiny gold and iron oxide particles to work as a team, then added antibody guides to steer the team through the bloodstream toward colorectal cancer cells. And in a nanosecond, the alloyed allies then kill the bad guys – cancer cells – with absorbed infrared heat.

This scenario is not science fiction – welcome to a medical reality.

“It’s a simple concept. It’s colloidal chemistry. By themselves, gold and iron-oxide alloys are benign and inert, and the infrared light is low-power heating,” said Carl Batt, Cornell’s Liberty Hyde Bailey Professor of Food Science and the senior author on the paper. “But put these inert alloys together, attach an antibody to guide it to the right target, zap it with infrared light and the cancer cells die. The cells only need to be heated up a few degrees to die.”

Batt and his colleagues – Dickson K. Kirui, Ph.D. ’11, a postdoctoral fellow at Houston Methodist Research Institute and the paper’s first author; Ildar Khalidov, radiology, Weill Cornell Medical College; and Yi Wang, biomedical engineering, Cornell – published their study in Nanomedicine (print edition, July 2013).

For cancer therapy, current hyperthermic techniques – applying heat to the whole body – heat up cancer cells and healthy tissue, alike. Thus, healthy tissue tends to get damaged. This study shows that by using gold nanoparticles, which amplify the low energy heat source efficiently, cancer cells can be targeted better and heat damage to healthy tissues can be mitigated. By adding the magnetic iron oxide particles to the gold, doctors watching MRI and CT scanners can follow along the trail of this nano-sized crew to its target.

When a near-infrared laser is used, the light penetrates deep into the tissue, heating the nanoparticle to about 120 degrees Fahrenheit – an ample temperature to kill many targeted cancer cells. This results in a threefold increase in killing cancer cells and a substantial tumor reduction within 30 days, according to Kirui. “It’s not a complete reduction in the tumor, but doctors can employ other aggressive strategies with success. It also reduces the dosage of highly toxic chemicals and radiation – leading to a better quality of life,” he explained.

Sea cucumber extract kills 95 percent of breast cancer cells and shrinks lung tumors .


A new study has shown that sea cucumber extract kills up to 95 percent of breast cancer cells, 90 percent of melanoma cells, 95 percent of liver cancer cells and 88 percent of lung cancer cells in vitro. The extract also stimulates the immune system against cancer and impedes key processes required for metastasis. While the science behind this is very new to Western medicine, the sea cucumber has been used in Chinese medicine for centuries.

cancer

Sea cucumber extracts potently kill multiple cancer cell lines

In previous studies, extracts of sea cucumber have demonstrated potent cytotoxicity against pancreatic, lung, prostate, colon, breast, skin and liver cancer cells as well as leukemia and gioblastoma. Researchers have identified a key compound responsible for sea cucumber’s anti-cancer properties: a triterpenoid known as frondoside A.

A new study has now confirmed the anti-cancer effects of frondoside A at a whole new level. In the lab, it has killed up to 95 percent of ER+ breast cancer cells, 90 percent of melanoma cells, 95 percent of liver cancer cells and 85-88 percent of three different lines of lung cancer. But the benefits of this compound don’t just stop at directly inducing programmed cell death (apoptosis). It also inhibits angiogenesis (the ability of tumors to grow new blood vessels to get their food) and stops cancer metastasizing by impeding cell migration and invasion. Even more intriguing is the ability of frondoside A to activate our immune system’s natural killer cells to attack cancer cells. This has been shown for breast cancer in particular but may also apply to all cancers, because it involves the immune system and not cancer cells directly. This may partially explain why frondoside A was so effective at shrinking lung tumors in mice that it rivaled chemo drugs in performance.

Lung tumor shrinkage that rivals chemo drugs – without the side effects

Frondoside A is potently cytotoxic to three different types of lung cancer in vitro, including NCI-H460Luc2, LNM35 (non-small cell lung cancer) and A459 (epithelial adenocarcinoma). And when given to mice with xenografted human non-small cell lung cancer, it shrank the tumors by 40 percent in 10 days. This compares very well with the shrinkage of 47 percent obtained with a standard chemo drug. But the similarities between the two compounds stop there. The chemo drug used in this study is known to damage DNA and carry potent negative side effects, such as kidney damage and immunosuppression, and it may actually induce leukemia in the patient. Frondoside A, however, actually stimulates the immune system, potently kills leukemia cells and produced no visible side effects in the mice, according to the researchers – all at a fraction of the price of chemo. But the most impressive part of this study was that this was achieved at a very small dose of frondoside A – equivalent to less than a single milligram for an adult human weighing 75 kilograms. It is also noteworthy that frondoside A given together with the chemo drug shrank the tumor by a remarkable 68 percent.

The future of sea cucumber as a natural medicine for cancer

Sea cucumber extract is a highly promising natural medicine for cancer. There are currently two clinical trials using it (with other natural extracts) against myeloma and multiple myeloma, but more trials against breast and lung cancer are clearly called for, as a start. In the meantime, dried and powdered sea cucumber is available in North America in over-the-counter health supplements aimed at inflammatory conditions (such as arthritis), because sea cucumber also happens to be a rich source of chondroitin.

Sources for this article include:

http://www.ncbi.nlm.nih.gov

http://www.ncbi.nlm.nih.gov

http://www.ncbi.nlm.nih.gov

http://www.ncbi.nlm.nih.gov

http://www.ncbi.nlm.nih.gov

http://www.clinicaltrials.gov

http://science.naturalnews.com

Learn more: http://www.naturalnews.com/042506_sea_cucumber_breast_cancer_cells_lung_tumors.html#ixzz2htDJU4Sl

Researchers Look to Single Cells for Cancer Insights


When asked about the biggest challenges to better understanding cancer, one word practically leaps from the mouths of many researchers: heterogeneity.

A tumor, the researchers stress, is not a uniform mass of identical cells with identical behaviors. Cells can act quite differently in one part of a tumor than in another. Genes critical to cell proliferation, for instance, may be active in one area but not another, or a subpopulation of cancer cells may be dormant, practically hiding from any drug that may try to enter their lair.

This heterogeneity has been blamed, for example, for the limited success of targeted therapies and of efforts to identify better diagnostic and prognostic markers of disease.

Researchers are now discovering what many have long suspected: much of what makes tumors heterogeneous overall is the substantial heterogeneity among individual cancer cells.

Until recently, the meticulous scrutiny of individual cells has been nearly impossible, particularly because of the relative scarcity in each cell of the key components that need to be measured, such as DNA and RNA. But thanks to technological advances that can help overcome some of those limitations, a growing number of investigators are beginning to delve deeper into the biology of the single cell.

The studies conducted to date “show us how much diversity there is among cancer cells in a given tumor,” said Dr. Garry Nolan, an immunologist at Stanford University whose lab is focused on mapping communication networks in individual cancer cells.

Even with improved technology, however, conducting studies at the single-cell level is difficult and can be time-consuming and expensive. But with growing interest—and $90 million over 5 years from the NIH Common Fund initiative (see the sidebar)—there is cautious optimism that over the next decade single-cell research may begin to pay dividends for patients with cancer and other diseases.

Moving beyond the Average

Most research on the molecular biology of tumors requires the use of mixtures of tens or hundreds of thousands of cells. Those samples “have immune cells, endothelial cells, and other infiltrating cells that make up the milieu of what a tumor actually is,” explained Dr. Dan Gallahan of NCI’s Division of Cancer Biology. “That really makes it difficult to get a grasp on what defines or, more importantly, how to treat a tumor.”

Results from studies that involve a bulk population of cells, Dr. Gallahan continued, essentially represent an average measurement.

Studying single cells is a way to “defy the average,” Dr. Marc Unger, chief scientific officer of Fluidigm Corporation, said earlier this year at a stem cell conference in Japan. (Fludigm, which develops tools for single-cell analysis, and the Broad Institute recently announced plans to establish a single-cell genomics research center.)

Single-cell analysis may be able to provide important clinical insights, said Dr. Nicholas Navin of the University of Texas MD Anderson Cancer Center, who has used next-generation sequencing to study variations in the number of genes (copy number variation) in single cancer cells.

Single-cell analysis might, for example, help identify “pre-existing [cell populations] that are resistant to chemotherapy or rare subpopulations that are capable of invasion and metastasis,” he said. “We may also be able to quantify the extent of heterogeneity in a patient’s tumor using single-cell data and use this index to predict how a patient will respond to treatment,” Dr. Navin continued.

Results from several recent studies have highlighted the challenges posed by tumor heterogeneity.

For example, researchers at BGI (formerly Beijing Genomics Institute) sequenced the protein-coding regions of DNA (the exome) of 20 cancer cells and 5 normal cells from a man with metastatic kidney cancer. The researchers found a tremendous amount of genetic diversity across the cancer cells, with very few sharing any common genetic mutations.

Much of the work in the analysis of single cells is still quite preliminary, and any potential clinical impact is still some years away, researchers agree.

“The problem with the single-cell data is that we don’t really know yet what they mean,” Dr. Sangeeta Bhatia of the Massachusetts Institute of Technology commented recently in Nature Biotechnology.

And studies involving bulk populations of cells will not be going away any time soon, noted Dr. Betsy Wilder, director of the NIH Office of Strategic Coordination, which oversees the NIH Common Fund.

“Single-cell analysis isn’t warranted for every question that’s out there,” Dr .Wilder stressed. “Studies using populations of cells will continue to be done, because it makes a lot of sense to do them.”

Technology, a Driving Force

Beyond just an interest in learning more about single cells—what Dr. Gallahan called “the operational units in biology”—technology has been the driving force behind the growth of this field.

Dr. Stephen Quake, also of Stanford, has pioneered the use of microfluidics, which typically uses small chips with microscopic channels and valves—often called lab-on-a-chip devices—that allow researchers to single out and study individual cells. Dr. Quake, who co-founded Fluidigm, and others are increasingly using these devices for gene-expression profiling and for sequencing RNA and DNA of individual cells.

Dr. Nolan’s research involves a hybrid approach that combines two technologies: a souped-up method of flow cytometry, which has been used for several decades to sort cells and to perform limited analyses of single cells, and mass spectrometry, which is often used to identify and quantify proteins in biological samples.

Dr. Nolan’s lab is using this “mass cytometry” approach—developed by Dr. Scott Tanner of the University of Toronto—to characterize the response of individual cells to different stimuli, such as cytokines, growth factors, and a variety of drugs. Much of the group’s work has focused on analyzing normal blood-forming cells.

They published an influential study last year in Science that revealed some of the subtle biochemical changes that occur during cell differentiation. The study also described how dasatinib (Sprycel), a drug used to treat chronic myelogenous leukemia, affects certain intracellular activities. The research, Dr. Nolan said, is a prelude to studying individual cells from patients with blood cancers. The approach, he believes, may prove particularly useful for identifying new drugs and for testing them in the lab.

A tumor is not a uniform mass of identical cells with identical behaviors. Cells can act quite differently in one part of a tumor than in another.

The Microscale Life Sciences Center (MLSC), an NIH Center of Excellence in Genomic Science that is housed at Arizona State University, develops and applies the latest technology to single-cell research.

The center—a collaboration of investigators from Arizona State, the University of Washington, Brandeis University, and the Fred Hutchinson Cancer Research Center—includes researchers from numerous disciplines, including microfluidics, computer science, physics, engineering, and biochemistry, explained principal investigator Dr. Deirdre Meldrum.

“All of these disciplines are needed to develop the new technologies we’re working on,” said Dr. Meldrum, an electrical engineer by training.

In its initial work, the MLSC has measured metabolic processes in single living cells, including cellular respiration—the process by which cells acquire energy—as it relates to an individual cell’s ability to resist or succumb to cell death. The workhorse of this effort is a platform called the Cellarium, developed by Dr. Meldrum’s team. Individual cells are isolated in controlled chambers, Dr. Meldrum explained, “where we perturb them and measure how they change over time.”

Investigators at the MLSC and elsewhere have also developed technologies to image single cells. MLSC scientists are using a device developed by VisionGate, called the Cell-CT, “that enables accurate measurement of cellular features in true 3D,” Dr. Meldrum said.

MLSC researchers have studied abnormal esophageal cells from people with Barrett esophagus, a condition that increases the risk of esophageal adenocarcinoma. In particular, they’ve looked at how these cells respond to very low oxygen levels, or hypoxia.

Acid reflux, which can cause Barrett esophagus, can damage the esophagus “and lead to transient hypoxia in the epithelial lining of the esophagus,” explained Dr. Thomas Paulson, an investigator at Fred Hutchinson. In effect, he continued, the Cellarium system provides a snapshot of how this hypoxic environment selects for variants of cells that are able to survive and grow in it, providing insights into the factors that influence the evolution of cells from normal to cancerous.

Although Dr. Paulson’s work at MLSC is focused on Barrett esophagus, he believes the approach represents an excellent model system for studying cancer risk in general.

“I think our understanding of what constitutes risk is probably going to change as we understand the types of changes that occur at the single-cell level” that can transform a healthy cell into a cancerous cell, he said.

Deeper Dives Ahead

There’s a general acknowledgement in the field that single-cell analysis still has important limitations. Technological improvements are needed that can allow for the same type of molecular and structural “deep dives” that can be achieved by studying batches of cells. And powerful computer programs will be needed to help interpret the data from single-cell studies.

In addition, the research will eventually have to move beyond the confines of the mostly artificial environments in which single cells are now being tested, Dr. Gallahan noted. “As the technology gets better, we should be able to do more of this work in an in vivo setting.”

Although much more work is needed, the potential for what can be learned from studying single cells is quite large, Dr. Nolan believes.

“The fact that we’ve been able to make good decisions and learn as much as we have, even at the level of resolution [of cell populations], means that there’s something of even greater value to mine when you get to the level of the single cell,” he said.

Transforming the Field of Single-Cell Research

This month, the National Institutes of Health will announce grant recipients for the NIH Common Fund’s single-cell analysis program.

The program, which includes three funding opportunities, “is largely a technology building program,” explained Dr. Wilder. The NIH Common Fund launched this program now because “there’s a sense that the technologies exist that can enable us to do the sort of analysis required to look at single cells in their native environment,” such as in a piece of excised tissue.

Although the focus is on technology, an important goal of the initiative is to support research that will “identify a few general principles of how single cells behave in a complex environment,” added Dr. Ravi Basavappa, the program director for the single-cell analysis program.

From the planning discussions, it was clear that the program should not limit the types of technology under consideration, Dr. Wilder commented. “Our analysis indicated that there are a lot of possibilities, so we left it up to the imaginations of the investigators to determine what technologies would be most transformative for the field as a whole.”

Source: NCI

Researchers Shed Light on Why Some Breast Cancers Spread to the Lungs.


Cancer experts have long known that virtually all cancers – regardless of the location of the primary tumor – have the ability to metastasize, or spread, to distant parts of the body. The lungs, bones, and liver are some of the more common sites of metastasis. But little is known about the biological mechanisms that fuel this spread of cancer cells.

Now, a team of scientists from Memorial Sloan-Kettering reports on recent findings from research in mice that provide new understanding about why breast cancer might spread to the lung. The investigators found that some breast cancer cells are dormant – meaning the cells are not dividing and are clinically undetectable – upon migrating to the lung, but may eventually start dividing to generate a new tumor. Their reactivation occurs as the cells produce and secrete a protein called Coco. This protein shuts down BMP, a protein that is produced by healthy lung cells and serves as an antitumor signal, preventing cancer growth.

Preferred Metastasis Sites

In laboratory experiments, the researchers stopped breast cancer cells from producing Coco and showed that this caused the cells to become dormant once more. The investigators note that these breast cancers rarely spread to the brain or bone – organs that do not produce the antitumor protein BMP.

“These findings suggest that different cancers may have preferred metastasis sites, which are dictated by the proteins its tumor cells produce. It’s possible that each organ has its own antitumor protein similar to BMP,” said cell biologist Filippo Giancotti, who led the study published in the August 17 issue of the journal Cell.

Next Steps

“Eventually, we may be able to identify and test for Coco-like tumor proteins, which could help predict if, when, and in what organ a cancer might metastasize,” he said. “In the future, it could also lead to the production of drugs that suppress Coco-like tumor proteins and possibly help prevent metastasis.”

The next step for Giancotti’s team is to develop a way to block Coco’s ability to inhibit BMP, with the goal of developing a therapy to prevent the spread of cancer from the breast to the lung. One way to achieve this may be through the generation of monoclonal antibodies, which are proteins engineered to attach to other proteins and block their function.

Source: MSKCC.